JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL.68,NO.19,2016 ª 2016 PUBLISHED BY ELSEVIER ON BEHALF OF THE ISSN 0735-1097/$36.00 AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION http://dx.doi.org/10.1016/j.jacc.2016.07.780 THE PRESENT AND FUTURE REVIEW TOPIC OF THE WEEK Therapeutic Fibrinolysis How Efficacy and Safety Can Be Improved Victor Gurewich, MD ABSTRACT Therapeutic fibrinolysis has been dominated by the experience with tissue-type plasminogen activator (t-PA), which proved little better than streptokinase in acute myocardial infarction. In contrast, endogenous fibrinolysis, using one-thousandth of the t-PA concentration, is regularly lysing fibrin and induced Thrombolysis In Myocardial Infarction flow grade 3 patency in 15% of patients with acute myocardial infarction. This efficacy is due to the effects of t-PA and urokinase plasminogen activator (uPA). They are complementary in fibrinolysis so that in combination, their effect is synergistic. Lysis of intact fibrin is initiated by t-PA, and uPA activates the remaining plasminogens. Knockout of the uPA gene, but not the t-PA gene, inhibited fibrinolysis. In the clinic, a minibolus of t-PA followed by an infusion of uPA was administered to 101 patients with acute myocardial infarction; superior infarct artery patency, no reocclusions, and 1% mortality resulted. Endogenous fibrinolysis may provide a paradigm that is relevant for therapeutic fibrinolysis. (J Am Coll Cardiol 2016;68:2099–106) © 2016 Published by Elsevier on behalf of the American College of Cardiology Foundation. n occlusive intravascular thrombus triggers fibrinolysis, as shown by it frequently not being A the cardiovascular diseases that are the lead- identified specifically in publications on clinical ing causes of death and disability worldwide. fibrinolysis. The only pharmacological means to remove the The anticipated benefits of t-PA were never ful- thrombus is fibrinolysis. There are 2 plasminogen filled, and it has been largely replaced by percuta- activators in the blood responsible for fibrinolysis: neous coronary intervention (PCI) as the treatment of tissue-type plasminogen activator (t-PA) and uroki- choice for AMI in urban centers in the United States, nase plasminogen activator (uPA). They exist in although it is still used in rural areas too far from a both single-chain and plasmin-cleaved 2-chain forms. catheterization facility. As pre-treatment, or facili- With t-PA, both forms have the same activity (1), tated PCI, t-PA significantly increased both throm- whereas the single-chain form of uPA is a proenzyme botic and hemorrhagic complications of PCI (7),and (pro-uPA) and the 2-chain form is an active enzyme itsusehasbeendiscouraged.Inischemicstroke,t-PA (2-chain uPA, the enzymatic form of uPA [tc-uPA]) (2). is used in only about 5% of patients (8), and in venous The fibrin specificity of t-PA is mediated by high thromboembolism, a hemorrhagic risk has limited its fibrin affinity (3,4), which promotes plasminogen use to patients with hemodynamic instability due to activating activity about a thousand-fold (5).Itwas the emboli (9). the first fibrin-specific plasminogen activator, and The enzymatic form of uPA, tc-uPA, has been became the first recombinant protein on the market known since the 1940s as a nonspecific activator, like (6). The clinical experience with t-PA in acute streptokinase (SK), which caused bleeding complica- Listen to this manuscript’s myocardial infarction (AMI), ischemic stroke, and tions. The single-chain uPA proenzyme, pro-uPA, was audio summary by venous thromboembolism has been extensive. As a not identifiedandisolateduntil1980(10).Ithasno JACC Editor-in-Chief result, t-PA became essentially equated with fibrin affinity, but is nevertheless fibrin specific (11). Dr. Valentin Fuster. From the Vascular Research Laboratory, Mount Auburn Hospital, Cambridge, Massachusetts, and Harvard Medical School, Cam- bridge, Massachusetts. Dr. Gurewich has reported that he has no relationships relevant to the contents of this paper to disclose. Manuscript received July 14, 2016; accepted July 20, 2016. 2100 Gurewich JACC VOL. 68, NO. 19, 2016 Improving Fibrinolysis NOVEMBER 8, 2016:2099– 106 ABBREVIATIONS Being a proenzyme, it remains inert in blood A special challenge for primary PCI treatment is AND ACRONYMS until it reaches a clot, a pharmacologically reducing the time to reperfusion. Reduction in AMI advantageous property. Unfortunately, this mortality is greatest if reperfusion is accomplished AMI = acute myocardial infarction property is undermined by dose-dependent within 1 to 2 h of symptom onset (27),andin plasma instability, because it activates patients who received reperfusion treatment within ICH = intracranial hemorrhage plasma plasminogen at certain therapeutic 70 min of symptom onset, the mortality was 1.2% PCI = percutaneous coronary intervention concentrations, and plasmin converts pro- (28). In animal models, the longer the coronary uPA to tc-uPA. For example, in a study occlusion, the less salvageable myocardium remains pro-uPA = proenzyme urokinase plasminogen where pro-uPA and SK were compared in (29). Therefore, pre-treatment was tested. activator AMI, bleeding complications occurred in 14% FACILITATED PCI WITH t-PA SK = streptokinase of the pro-uPA patients, of whom 4% tc-uPA = 2-chain urokinase required transfusions and 2 patients had an Although t-PA pre-treatment doubled the number of plasminogen activator, the intracranial hemorrhage (ICH) (12).Atphysi- enzymatic form of uPA patients with initial TIMI flow grade 3 patency, the ological and lower therapeutic concentra- TIMI = Thrombolysis In final TIMI flow grade 3 patency rates did not differ in tions, pro-uPA is stable in plasma and is an Myocardial Infarction the 2 groups (89% vs. 88%), consistent with t-PA’s essential component of the endogenous t-PA = tissue-type significant rethrombosis rate (17). In addition, more plasminogen activator fibrinolytic system. bleeding, reinfarctions, and strokes occurred with uPA = urokinase plasminogen FIBRINOLYSIS WITH t-PA facilitated PCI (30). By contrast, with pro-uPA, neither activator a prothrombotic effect nor reocclusions were found in The U.S. Food and Drug Administration approved AMI (31), suggesting that the complications were t-PA for AMI treatment in 1987 but, to show that it related to t-PA rather than to fibrinolysis. reduced mortality compared with SK, additional It was concluded that t-PA facilitated PCI offered clinical trials were performed starting in 1990. Three no benefit, an outcome lamented in a commentary in megatrials with an unprecedented total of 95,740 a prominent journal as “Facilitated angioplasty: patients were required before a significant p value paradise lost” (32), because there is no alternative to was reached for a mortality difference (13–15).This shorten the time to reperfusion. was in only 1 of 4 groups in the last trial, in which an Interestingly, these studies found that in 15% of accelerated rate of t-PA infusion induced a significant patients with ST-segment elevation myocardial 30-day mortality difference (6.3% vs. 7.0%) (15).Also infarction, TIMI flow grade 3 was already found at the unexpected was the finding that the ICH rate was time of the primary PCI (33), and these patients fared significantly higher with t-PA than SK, despite the significantly better (24,25). This illustrates the effi- nonspecific and indirect mode of action of SK. These cacy of endogenous fibrinolysis in which the t-PA results did not stand up to a Bayesian analysis, which concentration is $1,000-fold lower than the thera- concluded, “the clinical superiority of t-PA over SK peutic one. remains uncertain” (16). t-PA FIBRINOLYSIS INISCHEMICSTROKE As heralded by these trials, t-PA’s limited efficacy— a16Æ 10% reocclusion rate (17)—prothrombotic he- In ischemic stroke, a t-PA dose reduction was matologic effects, such as thrombin generation and required due to a 20% symptomatic ICH incidence platelet activation (18–22), and bleeding side effects, whentheusualAMIdosewasused(34).Asaresult, such as ICH, led to alternative therapies. the t-PA recanalization decreased 30% to 40%, PCI VERSUS t-PA making it ineffective for larger thrombi in proximal occlusions (35,36).Evenatthereduceddose,the In a review of 23 PCI trials involving 7,739 patients, symptomatic ICH rate was 6% to 7% (37). 3,867 were randomized to treatment with fibrinolysis In the largest trial, 1,500 patients per group were (2,939 with t-PA, 928 with SK) and 3,872 patients to randomized to t-PA or standard care and treated within primary PCI (23).Asignificantly better outcome was 6 h. The proportion of patients alive and living inde- obtained with PCI for both the short-term and long- pendently at 6 months was 37% with t-PA and 35% term outcomes. The post-treatment Thrombolysis In for the controls. Although insignificant, a secondary Myocardial Infarction (TIMI) flow grade 3, an impor- ordinal analysis found a significant (p < 0.001) favor- tant predictor of good outcome (24,25),wasalso able shift in the functional score in the t-PA–treated significantly better with PCI than in the GUSTO (Global patients, but more patients died with t-PA in the first Utilization of Streptokinase and Tissue Plasminogen 7days(11%vs.7%;p¼ 0.001) (38).Theauthors Activator for Occluded Coronary Arteries) trial (26). concluded that early treatment with t-PA should be JACC VOL. 68, NO. 19, 2016 Gurewich 2101 NOVEMBER 8, 2016:2099– 106 Improving Fibrinolysis encouraged, but others were more skeptical, including Catheter placement within the thrombus is a prereq-